ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1340G>A (p.Arg447Gln) (rs760676955)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219262 SCV000273980 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-24 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000555662 SCV000622247 uncertain significance Ataxia-telangiectasia syndrome 2019-07-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 447 of the ATM protein (p.Arg447Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs760676955, ExAC 0.02%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 230430). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000219262 SCV000687301 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193008 SCV001361527 uncertain significance not specified 2019-04-01 criteria provided, single submitter clinical testing Variant summary: ATM c.1340G>A (p.Arg447Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246090 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1340G>A in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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